Indwelling medical devices including vascular catheters are becoming essential in the management of hospitalized patients by providing venous access. The benefit derived from these catheters as well as other types of catheters such as peritoneal catheters, cardiovascular, orthopedic and other prosthetic devices is often upset by infectious complications. The most common organisms causing these infectious complications are Staphylococcus epidermidis and Staphylococcus aureus. In the case of vascular catheters, these two organisms account for almost 70-80% of all infectious organisms, with Staphylococcus epidermidis being the most common organism. Candida albicans, a fungal agent, account for about 10-15% of catheter infections.
Colonization of bacteria on the interior surfaces of the catheter or other part of the device can produce serious patient problems, including the need to remove and/or replace the implanted device and to vigorously treat secondary infective conditions. A considerable amount of attention and study has been directed toward preventing such colonization by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices. In such attempts the objective has been to produce a sufficient bacteriostatic or bactericidal action to prevent colonization.
Vancomycin was thought to be the logical antibiotic to use since it is the antibiotic of choice to treat systemic staphylococcal infections, particularly methicillin resistant S. epidermidis and S. aureus. However, vancomycin has several limitations:
(a) While several investigators have shown that vancomycin is active against nonadherent staphylococci in vitro and human tissue, it is not active against the staphylococci that adhere to foreign bodies and embed themselves in a layer of biofilm. The biofilm (slime or fibrous glycocalix) not only acts as a shield protecting the adherent staphylococci from vancomycin, but also inhibits the activity of glycopeptide antibiotics (vancomycin and teicoplanin). See e.g. Farber et al. J. Infect. Dis. 161:37-40 (1990); and Evans et al., Antimicrob. Agents Chemother. 31:889-894 (1987). PA0 (b) Using vancomycin prophylactically on a highly colonized surface (such as a catheter) will lead to the emergence of vancomycin resistant staphylococci, and would deprive the clinician of the only available therapeutic choice (glycopeptide antibiotics such as vancomycin and teicoplanin) should these resistant staphylococci cause bacteremia or deep seated infection. PA0 (c) Vancomycin has no activity on Candida albicans; its use would decrease the rate of staphylococcal device related infections at the expense of increasing the more complicated fungal superinfections.
Recent investigations into catheter associated infections have shown that bacterial produced adherent biofilms promote staphylococcal and Pseudomonas tolerance to antibiotics normally effective against the same bacteria systemically or in tissue. A dramatic representation of this problem was demonstrated by the inability of tobramycin to kill Pseudomas aeruginosa cells embedded in a biofilm at antibiotic levels of greater than 50 times the minimum bactericidal concentration (MBC) for the identical strain grown in liquid suspension. Nickel et al., Antimicrob. Agents Chemother. 27:619-624 (1985). Similarly, six weeks of intensive antibacterial chemotherapy with a .beta. lactam antibiotic, to which laboratory cultures were exquisitely sensitive, failed to prevent frequent recurrences of a S. aureus bacteremia originating from an endocardial pacemaker. Direct examination of the tip of the pacemaker lead, revealed that the staphylococci grew in phenomenally thick slimed enclosed biofilm which protected the bacteria from very high tissue levels of antibiotic. Subsequent in vitro studies showed the biofilm adherent bacteria were resistant to levels of antibiotics 50 to 100 times higher than the MBC needed to kill nonbiofilm encased cells of the same strain. Khoury, A. E. and Costeron J. W., "Bacterial Biofilms in Nature and Disease," Dialogues in Pediatric Urology, Vol. 14:2-5 (1991).
Although a considerable amount of attention and study has been directed toward preventing such colonization by the use of antimicrobial agents coated to indwelling medical devices, the need persists for improved means to combat bacterial colonization of such devices.